Beruflich Dokumente
Kultur Dokumente
Center for Muscle Biology, University of Kentucky, Lexington, Kentucky; 2Department of Physiology, College of Medicine,
University of Kentucky, Lexington, Kentucky; and 3Department of Rehabilitation Sciences, College of Health Sciences,
University of Kentucky, Lexington, Kentucky
Chaillou T, Lee JD, England JH, Esser KA, McCarthy JJ. Time
course of gene expression during mouse skeletal muscle hypertrophy.
J Appl Physiol 115: 10651074, 2013. First published July 18, 2013;
doi:10.1152/japplphysiol.00611.2013.The purpose of this study
was to perform a comprehensive transcriptome analysis during skeletal muscle hypertrophy to identify signaling pathways that are
operative throughout the hypertrophic response. Global gene expression patterns were determined from microarray results on days 1, 3, 5,
7, 10, and 14 during plantaris muscle hypertrophy induced by synergist ablation in adult mice. Principal component analysis and the
number of differentially expressed genes (cutoffs 2-fold increase or
50% decrease compared with control muscle) revealed three gene
expression patterns during overload-induced hypertrophy: early (1
day), intermediate (3, 5, and 7 days), and late (10 and 14 days)
patterns. Based on the robust changes in total RNA content and in the
number of differentially expressed genes, we focused our attention on
the intermediate gene expression pattern. Ingenuity Pathway Analysis
revealed a downregulation of genes encoding components of the
branched-chain amino acid degradation pathway during hypertrophy.
Among these genes, five were predicted by Ingenuity Pathway Analysis or previously shown to be regulated by the transcription factor
Kruppel-like factor-15, which was also downregulated during hypertrophy. Moreover, the integrin-linked kinase signaling pathway was
activated during hypertrophy, and the downregulation of musclespecific micro-RNA-1 correlated with the upregulation of five predicted targets associated with the integrin-linked kinase pathway. In
conclusion, we identified two novel pathways that may be involved in
muscle hypertrophy, as well as two upstream regulators (Kruppel-like
factor-15 and micro-RNA-1) that provide targets for future studies
investigating the importance of these pathways in muscle hypertrophy.
transcriptome; branched-chain amino acid; KLF15; ILK signaling;
micro-RNA-1
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isoflurane at 0.5 l/min), and the entire soleus was carefully removed
along with the majority of the gastrocnemius muscle. Particular
attention was made to ensure that the neural and vascular supply of the
plantaris muscle was not damaged during the excision of the synergist
muscles. Following recovery from surgery, mice were anesthetized at
the designated time point by an intraperitoneal injection of ketamine
(100 mg/kg) and xylazine (10 mg/kg), and plantaris muscles were
excised, weighed, placed in RNAlater (Ambion, Austin, TX), and
stored at 4C until use. Plantaris muscle was collected at 1, 3, 5, 7, 10,
and 14 days after the surgery (d1, d3, d5, d7, d10, and d14, respectively; n 6 per group). Control plantaris muscle (n 6) was
collected from mice subjected to a sham synergist ablation surgery.
Following collection of the plantaris muscle, mice were killed by
cervical dislocation under anesthesia.
RNA Isolation
Total RNA was prepared from plantaris muscle using TRIzol
reagent (Invitrogen, Carlsbad, CA) according to the manufacturers
directions. RNA samples were treated with TURBO DNase (Ambion,
Austin, TX) to remove genomic DNA contamination. The total RNA
concentration and purity were assessed by measuring the optical
density (230, 260, and 280 nm) with the Nanodrop 1000 Spectrophotometer (ThermoFisher Scientific, Wilmington, DE). RNA integrity
was assessed using the Agilent 2100 Bioanalyzer (Agilent Technologies, Palo Alto, CA); the average RNA integrity number value for all
samples was 9.46 0.10 (scale 110), indicating high-quality RNA
with minimal degradation products.
Microarray and Microarray Data Analysis
The microarray hybridization and processing were performed at the
University of Kentucky Microarray Core Facility, according to the
manufacturers protocol (Affymetrix, Santa Clara, CA). For each time
point, two Affymetrix chips (mouse gene 1.0 ST) were used with 250
ng of total RNA derived from a pooled sample of either the right or
left plantaris muscles from six animals. We pooled RNA samples
based on the experimental results reported by Kendziorski et al. (12),
showing that gene expression from RNA pools are similar to averages
of individuals that comprise the pool. The mouse gene 1.0 ST chip
provides coverage of 28,000 protein coding transcripts and 7,000
noncoding transcripts of which 2,000 are long intergenic noncoding
transcripts. Then the gene expression obtained from the two chips
(replicates of the pooled RNA samples from the same animals, with
each pooled sample derived from separate plantaris muscles) at each
time point was averaged and uploaded to Partek Genomics Suite (St.
Louis, MO) to identify differentially expressed genes; the criteria for
a gene to be considered differentially expressed was a twofold or
greater increase or a 50% decrease in expression in the experimental
group relative to the control group. At this step, we did not set a lower
cutoff for the signal intensity to avoid excluding low expressed genes
that might show a significant upregulation in response to functional
overload. All of the microarray data obtained in this study are
available by using GEO accession number GSE47098 (available at
http://www.ncbi.nlm.nih.gov/geo). Ingenuity Pathway Analysis (IPA;
Ingenuity Systems, Redwood, CA) was then used to identify those
pathways that were significantly enriched in the list of differentially
expressed genes associated with skeletal muscle. The IPA program is
based on the Ingenuity Knowledge Base, which consists of millions of
relationships (between genes, protein complexes, and networks) extracted from peer-reviewed scientific literature (2). As miR-1 was
identified by IPA to target some upregulated transcripts associated
with ILK signaling (see RESULTS), we expanded our analysis and
confirmed this prediction by using the online miRNA database TargetScan 6.2 (14).
Chaillou T et al.
day 7
day 14
day 10
control
24
day 5
PC #2 24.5%
-3
day 3
-31
-60
-87
-115
-143
-171
day 1
-200
-140
-100
-61
-22
16
55
94
133
172
211
250
PC #1 43.7%
Fig. 1. A two-dimensional principal component analysis (PCA) mapping of the
variance in gene expression during hypertrophy. The distribution of each group
along the first component (x-axis, PC #1) suggested that the imposition of
synergist ablation had the greatest effect on gene expression variability
(43.7%). The distribution of groups along the second component (y-axis, PC
#2) indicated that the length of time that synergist ablation was applied had the
second greatest influence on the variability of gene expression (24.5%).
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Chaillou T et al.
2000
Number of genes
Down-regulated
Up-regulated
1600
1200
800
400
0
d1
d3
d5
d7
d10
d14
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Category
Canonical pathway
Immune response
Chaillou T et al.
d1
d3
21
Hepatic Cholestasis
Role of Macrophages, Fibroblasts and Endothelial Cells in Rheumatoid
Arthritis
Type I Diabetes Mellitus Signaling
26
42
19
11
25
IL-6 Signaling
28
1
0
iNOS Signaling
12
Macropinocytosis Signaling
12
NF-B Signaling
31
PPAR Signaling
24
VDR/RXR Activation
15
d5
d7
Mitochondrial Dysfunction
39
36
39
I L K S ig na l i n g
26
10
32
10
33
11
Valine Degradation I
10
11
11
10
11
10
Metabolism
d10
d14
20
C e l l u la r s t r es s an d in j ur y
26
28
30
31
26
25
Im m un e r e sp o ns e
T H e lp e r C e l l D if f e r e n t i a t i o n
17
17
15
14
12
11
21
12
25
20
23
25
20
28
15
19
11
14
LXR/RXR Activation
22
23
19
11
18
15
14
11
11
10
Early pattern
Late pattern
Intermediate pattern
Common
Fig. 3. Canonical pathways associated with skeletal muscle in response to mechanical overload. The top statistically significant canonical pathways were
identified from IPA, using a right-tailed Fishers exact and a P value 0.001 [-log(P value) 3]. The pathways presented represent the pathways specific to
the early (d1), intermediate (d3 d7), and late (d10 d14) gene expression patterns, and those pathways identified across all three patterns. The numbers represent
the numbers of either upregulated (1) or downregulated (2) genes associated with a specific pathway. iNOS, inducible nitric oxide synthase; PPAR, peroxisome
proliferator-activated receptor signaling; VDR, vitamin D receptor; RXR, retinoid X receptor; ILK, integrin-linked kinase; LXR, liver X receptor.
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Chaillou T et al.
Symbol
Enzyme
BCAT2*
BCKDHA
BCKDHB
DBT
DLD*
AUH*
EHHADH*
HADHA*
Enoyl-CoA hydratase
HIBCH
3-Hydroxyisobutyryl-CoA hydrolase
HIBADH
3-Hydroxyisobutyrate dehydrogenase
HADHB*
Gene Name
Member of
d3
d5
d7
0.48
0.51
0.51
2-Oxoisovalerate dehydrogenase
0.38
0.35
0.46
0.36
0.38
0.36
0.48
0.42
0.39
0.38
0.49
0.43
0.35
0.49
0.51
0.40
0.46
0.52
0.38
0.42
0.49
0.34
0.37
0.35
3-Hydroxyisobutyryl-CoA hydrolase
0.40
0.42
0.43
3-Hydroxyisobutyryl-CoA dehydrogenase
0.47
0.50
0.49
The nos. represent the fold change of gene expression after 3, 5 and 7 days (d3, d5, d7, respectively) of mechanical overload compared with control
non-overloaded muscles. Italicized numbers mean that the fold change in gene expression is lower than 50% decrease. The selected genes were differentially
expressed (twofold increase or 50% decrease) at least one time between d3 and d7. *Genes also associated with the isoleucine degradation pathway. Genes also
associated with the leucine degradation pathway.
Enzymatic complex
Gene
Branched-chain-aminoacid transaminase
BCAT2
2-oxoisovalerate
dehydrogenase
BCKDHA
BCKDHB
DBT
DLD
L-valine
2-oxoisovalerate
Isotyryl-CoA
2-methylacyl-CoA
dehydrogenase
Methylacrylyl-CoA
Enoyl-CoA
hydratase
AUH
EHHADH
HADHA
HADHB
3-hydroxyisobutyrylCoA hydrolase
HIBCH
3-hydroxyisobutyryl-CoA
dehydrogenase
HIBADH
3-hydroxyisobutyryl-CoA
3-hydroxyisobutyrate
3-amino-2-methyl
propionate transaminase
Methylmalonatesemialdehyde
3-amino-2methylpropanoate
Methylmalonate-semialdehyde
dehydrogenase
Propanoyl-CoA
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Chaillou T et al.
ILK Pathway
DISCUSSION
1.2
mRNA levels
d7
1.0
0.8
0.6
**
0.4
0.2
***
0.0
KLF15
BCAT2
EHHDAH
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Chaillou T et al.
Symbol
Gene Name
Member of/Molecule
d3
d5
d7
Binding protein
IRS1
SH2B2
TMSB10/TMSB4X
IRS
IRS
TMSB4
0.50
2.25
6.41
0.77
2.03
9.05
0.96
1.77
8.47
Cyclin
CCND1
Cyclin D1
CCND1
3.99
3.35
3.13
Cytokine
TNF
TNF
2.30
1.78
1.34
Cytoskeleton protein
ACTG1
ACTG2
ACTN4
FBLIM1
FLNA
FLNB
MYH9
PARVA
VIM
Actin, 1
Actin, 2, smooth muscle, enteric
Actinin, 4
Filamin binding LIM protein 1
Filamin A,
Filamin B,
Myosin, heavy chain 9, nonmuscle
Parvin,
Vimentin
F-Actin
G-Actin/F-Actin
-Actinin
Filanin
Filanin
Filanin
Myosin
PARVA
Vimentin
2.11
0.93
2.03
2.40
2.45
2.50
3.08
2.26
2.15
2.16
2.05
2.14
2.91
2.92
2.94
3.25
2.98
2.16
2.19
2.82
2.32
2.91
3.52
3.17
3.44
3.19
2.20
Enzyme
FNBP1
PTGS2
RHOB
RHOC
RHOU
RND3
Ras homolog
PTGS2
Ras homolog
Ras homolog
Ras homolog
Ras homolog
2.02
6.92
1.64
2.90
0.72
1.87
2.20
8.21
1.98
3.05
0.55
2.26
2.43
8.67
2.19
2.72
0.46
2.64
FN1
Fibronectin 1
Fibronectin 1
3.10
3.91
4.32
Growth factor
PDGFC
VEGFA
VEGFB
VEGF
VEGF
VEGF
2.98
0.57
0.42
4.72
0.39
0.38
5.27
0.28
0.32
Kinase
AKT1
ILK
MAP2K6
MAPK12
PIK3C2A
PIK3R3
RPS6KA5
AKT
ILK
MAP2K6
JNK
PI3K
PI3K
MSK1/2
1.90
1.92
0.18
0.60
1.56
0.93
0.42
2.11
2.28
0.24
0.58
1.87
1.82
0.49
2.17
2.53
0.26
0.49
2.23
2.54
0.57
Peptidase
CASP3
CASP3
2.42
2.85
2.95
Phosphatase
PPAP2B
PPM1J
PPM1L
PPP2R1B
PPAP2B
PP2A
PP2A
PP2A
2.35
0.44
0.23
2.38
2.60
0.41
0.24
2.27
2.57
0.33
0.26
2.28
Sarcomeric protein
ACTC1
ACTA2
MYH11
MYH4
MYH7
MYH8
MYL2
MYL3
MYL4
G-Actin/F-Actin
G-Actin/F-Actin
Myosin
Myosin
Myosin
Myosin
Myosin
Myosin
Myosin
1.68
1.04
0.38
0.68
0.28
0.93
0.24
0.14
2.31
5.39
2.02
0.43
0.56
0.39
3.63
0.32
0.11
5.79
6.47
2.20
0.49
0.50
0.57
6.09
0.18
0.10
6.39
Transcription regulator
HIF1A
MYC
SNAI1
SNAI2
HIF1A
MYC
SNAI1
SNAI2
3.20
8.43
2.96
2.15
3.55
5.93
2.47
4.36
3.79
4.89
1.92
4.54
Transmembrane receptor
TNFRSF1A
TNFR
2.69
2.46
2.21
The nos. represent the fold change of gene expression after d3, d5, and d7 of mechanical overload compared with control non-overloaded muscles. Italicized
numbers mean that the fold change in gene expression is either lower than 50% decrease or lower than 2-fold increase. The selected genes were differentially
expressed (twofold increase or 50% decrease) at least one time between d3 and d7.
Here, we showed that several components of the valine degradation pathway are downregulated during the intermediate
gene expression pattern in response to mechanical overload
(Table 1). Interestingly, some of these genes also encode
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Extracellular space
Cytoplasm
Chaillou T et al.
ECM
protein
Growth
factors
Integrin
RTK
IRS
PARVA
Increased in Ov muscle
PI3K
Increased or decreased
in Ov muscle
ILK
GSK3
Activates
-Actinin
SNAI2
CTN
Inhibits
Binding
Actin
Filamin
Actin
Vimentin
FN1
Myosin
ECM
Sarcomere
CCND1
MYC
Myosin
Cytoskeleton
Cell proliferation
Fig. 6. Schematic representation of the ILK signaling and its putative regulation by the micro-RNA-1 (miR-1). This pathway was adapted from the pathway
determined by Ingenuity Pathway Analysis and represents the main genes differentially regulated in response to 37 days of mechanical overload. The gene
expression of these components of ILK signaling was determined by microarray and is presented in Table 2. As shown in Table 2, the gene expression of two
members of insulin receptor substrate (IRS) family, IRS1 and SH2B2, is decreased and increased, respectively (represented by green in the figure). The gene
expression of some components of myosin is either increased or decreased (represented by green in the figure; gene expression presented in Table 2). The genes
designated in purple are predicted targets of miR-1. ECM, extracellular matrix; PARVA, parvin-; RTK, receptor tyrosine kinase; PI3K, phosphoinositide
3-kinase; GSK3, glycogen synthase kinase 3; FN1, fibronectin 1; SNAI2, snail homolog 2; CTN-, -catenin; CCND1, cyclin D1; MYC, v-myc myelocytomatosis viral oncogene homolog.
components essential for the degradation of leucine and isoleucine, the two other BCAAs. Moreover, we showed that
mRNA expression of the transcription factor Klf15 is significantly downregulated during hypertrophy, which correlated
control
d3
d5
5
4
1.0
0.8
0.6
0.4
**
0.2
0.0
mRNA levels
d7
1.2
miR-1 levels
1.4
0
miR-1
PARVA
SNAI2
Fig. 7. Quantitative PCR of expression of miR-1 and genes involved in the ILK
signaling pathway (PARVA and SNAI2). miR-1 was predicted by targetScan algorithm
to bind PARVA and SNAI2. All results are expressed as means SE (n 6 at each
time point). *Significantly different from the control non-overloaded muscle (d0).
with the reduced expression of four of its IPA-predicted targets: Ehhadh, Hadha, and Hadhb (3 components of enoyl-CoA
dehydrogenase, a valine and isoleucine-degrading enzymatic
complex), and Acadm (a component of a leucine-degrading
enzymatic complex). In addition to these genes, Bcat2, which
encodes the protein that catalyzes the initial step for the
degradation of all BCAAs, is also downregulated with hypertrophy and has been reported to be regulated by Klf15 in
skeletal muscle (28).
There is accumulating evidence that Klf15 is capable of
influencing muscle mass by regulating the expression of genes
that are part of the BCAA degradation pathway. The inactivation of Klf15 resulted in a modest but significant increase in
lean mass that was associated with a reduced expression of
multiple genes encoding amino acid-degrading enzymes, including Bcat2 (8). However, a more recent study from this
same group reported no change in skeletal muscle mass (9),
while Klf15 null mice developed a severe cardiac hypertrophy
in response to pressure overload (6). Alternatively, Klf15
overexpression was shown to accelerate catabolism of BCAA,
resulting in myotube and skeletal muscle atrophy (28). Elevated levels of Klf15 also suppressed mTOR activity in myotubes (28), a central regulator of protein synthesis shown to be
Chaillou T et al.
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